The present invention is directed to novel compounds and pharmaceutical compositions that inhibit the binding of the chemoattractant peptide chemerin to the G-protein coupled receptor (GPCR) ChemR23. These compounds are useful in preventing inflammatory diseases including, but not limited to, psoriasis, dermatomyositis, systemic lupus erythematosus (SLE), arthritis, multiple sclerosis and conditions of metabolic syndrome including, but not limited to, obesity, insulin resistance, cardiovascular disease, and cholesterol transport and metabolism.
Plasmacytoid dendritic cells (pDC) represent a small (<0.5%) but versatile subset of circulating leukocytes functioning at the interface between adaptive and innate immunity. pDC are present in diverse tissue sites, often associated with general inflammation as well as lymphocyte infiltrates, and have been reported in reactive tonsils, inflamed nasal mucosa, thymus, cutaneous lesions (herpes zoster, skin blisters, psoriasis vulgaris, lupus erythematosus, contact dermatitis, but not atopic dermatitis, melanoma), peritoneal lavage fluid, and ovarian epithelial tumors.
ChemR23, also called CMKLR1, ChemerinR, and Dez is a G protein coupled receptor related to GPR-1 (38% overall amino acid identity), C3a receptor (38%), C5a anaphylatoxin receptor (36%) and formyl Met-Leu-Phe receptors (35%). ChemR23 is more distantly related to the chemokine receptors subfamily (Methner A, Hermey G, Schinke B, Hermans-Borgmeyer I. (1997) Biochem Biophys Res Commun 233:336-42; Samson M, Edinger A L, Stordeur P, Rucker J, Verhasselt V, Sharron M, Govaerts C, Mollereau C, Vassart G, Doms R W, Parmentier M. (1998) Eur J. Immunol 28:1689-700). ChemR23 transcripts were found to be abundant in monocyte-derived dendritic cells and macrophages, plasmacytoid DC (pDC), and natural killer (NK) cells. Low expression can also be detected by reverse transcription-PCR in CD4+ T lymphocytes. The gene encoding ChemR23 maps to the q21.2-21.3 region of human chromosome 12, outside the gene clusters identified for chemoattractant receptors. It is a putative chemoattractant receptor and it may play a crucial role in the recruitment and/or trafficking of leukocyte cell populations. ChemR23, by its specific expression in immature dendritic cell populations, as well as macrophages, is an attractive candidate receptor involved in the initiation and early regulation of immune responses.
The ligand for ChemR23, chemerin, was identified as a cDNA which is up-regulated by the treatment of skin raft cultures with the retinoic acid receptor (RAR) beta/gamma-selective anti-psoriatic synthetic retinoid, tazarotene [AGN 190168/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate] (Nagpal S, Patel S, Jacobe H, DiSepio D, Ghosn C, Malhotra M, Teng M, Duvic M, Chandraratna R A. (1997) J. Invest Dermatol 109: 91-5). Chemerin is first produced as a preprochemerin which undergoes proteolytic processing to reveal agonistic properties at ChemR23. The gene for preprochemerin is located at the 17p13.3 position. Preprochemerin cDNA is 830 bp long and encodes a putative protein product of 163 amino acids.